Study co-author Carolyn Owen, MD: “The regimen of idelalisib plus ofatumumab was effective, leading to durable remissions even in high-risk patients, including those with del17p, refractoriness to fludarabine, and unmutated IgVH status. The toxicities were not significantly different from those seen with the combination of idelalisib plus rituximab, to which most physicians are more accustomed. While [studies comparing these two regimens] cannot be directly compared, there appeared to be a difference favoring ofatumumab over rituximab as the monoclonal antibody partner.”
Results from a phase III randomized controlled trial show that adding the anti-CD20 monoclonal antibody ofatumumab to idelalisib improves progression-free survival (PFS), compared with ofatumumab alone, for patients with relapsed chronic lymphocytic leukemia (CLL). The study, published in The Lancet Haematology, suggests that this combination represents a new treatment option for patients with relapsed CLL – even for patients with high-risk disease.
Jeffrey Jones, MD, in the division of Hematology at Ohio State University, and researchers evaluated the combination of idelalisib and ofatumumab in 261 patients with relapsed CLL that had progressed less than 24 months from the last line of therapy. Patients who were refractory to ofatumumab were excluded from the study.
Between December 17, 2012, and March 31, 2014, the authors enrolled 261 patients (median age = 68 years [range = 61-74 years]). Patients had received a median of three previous therapies (range = 2-4 therapies).
Patients were randomized 2:1 to receive either:
- oral idelalisib 150 mg twice-daily plus intravenous (IV) ofatumumab 300 mg in week 1, then 1,000 mg weekly for 7 weeks, then every 4 weeks for 16 weeks
- IV ofatumumab 300 mg IV in week 1, then 2,000 mg weekly for 7 weeks, and every 4 weeks for 16 weeks
The median PFS (assessed by an independent review committee) was twice as long in the combination group than the ofatumamab-alone group: 16.3 months (range = 13.6-17.8 months) versus 8 months (range = 5.7-8.2 months), for an adjusted hazard ratio of 0.27 (95% CI 0.19-0.39; p<0.0001), after adjusting for relapsed or refractory disease status, the presence of del17p or TP53 mutation, and IGHV mutation status.
The most frequently reported grade ≥3 adverse events (AEs) in the combination group were neutropenia (34%; n=59), diarrhea (20%; n=34), and pneumonia (14%; n=25); in the ofatumumab-alone group, the most frequently reported grade ≥3 AEs were neutropenia (16%; n=14), pneumonia (8%; n=7), and thrombocytopenia (7%; n=6).
The toxicity profiles of each treatment approach were similar, the authors reported. However, serious infections occurred more frequently in the combination than the ofatumumab group, including pneumonia (13% vs. 10%), sepsis (6% vs. 1%), and Pneumocystis jirovecii pneumonia (5% vs. 1%).
A total of 28 treatment-related deaths were reported: 22 in the idelalisib combination group (most commonly due to sepsis and pneumonia) and six in the ofatumumab-alone group (mostly due to progressive multifocal leukoencephalopathy and pneumonia).
“The major limitation of the study is the same that would be argued for many recent studies, which is that the comparator arm is not really relevant to the current treatment landscape,” study co-author Carolyn Owen, MD, told ASH Clinical News. “This study demonstrates the efficacy and relative tolerability of idelalisib plus ofatumumab, but it comes at a time when ibrutinib is a standard of care treatment that was not available at the time of the study, making it hard to figure out where to consider placing this regimen.”
Source: Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. 2017; 4:e114–26.